The Safety, Pharmacokinetics and Antitumor Activity of BGB-A317 in Combination With BGB-290 in Subjects With Advanced Solid Tumors

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A Phase 1/1b, Open Label, Multiple Dose, Dose Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics and Antitumor Activity of the Anti-PD-1 Monoclonal Antibody BGB-A317 in Combination With the PARP Inhibitor BGB-290 in Subjects With Advanced Solid Tumors

Part A: Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 [ Time Frame: from the day of first administration of study drugs up to 30 days after the last administration of BGB-290 and up to 120 days after the last administration of BGB-A317 ]

Safety and tolerability as assessed by the incidence and nature of AEs.

Part A: Incidence and nature of Dose Limiting Toxicities [ Time Frame: from the day of first administration of study drugs up to 30 days after the last administration of BGB-290 and up to 120 days after the last administration of BGB-A317. ]

Part A: Determination of maximum tolerated dose of the combination of BGB-A317 and BGB-290 [ Time Frame: from the day of first administration of study drugs up to 30 days after the last administration of BGB-290 and up to 120 days after the last administration of BGB-A317. ]

Part B: Disease response as determined by Overall Response Rate per RECIST Version 1.1 [ Time Frame: From randomisation until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment. ]

Anti-tumor activity as determined by the ORR. Radiological assessment of tumor response should be performed approximately every 9 ± 1 weeks in the first 12 months and approximately every 12 ± 1 weeks from screening until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.

Part B: Disease response as determined by Progression Free Survival per RECIST Version 1.1 [ Time Frame: From randomisation until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment. ]

Anti-tumor activity as determined by the PFS. Radiological assessment of tumor response should be performed approximately every 9 ± 1 weeks in the first 12 months and approximately every 12 ± 1 weeks from screening until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.

Part B: Disease response as determined by Duration of Response per RECIST Version 1.1 [ Time Frame: From randomisation until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment. ]

Anti-tumor activity as determined by the DOR. Radiological assessment of tumor response should be performed approximately every 9 ± 1 weeks in the first 12 months and approximately every 12 ± 1 weeks from screening until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.

Part B: Disease response as determined by Disease Control Rate per RECIST Version 1.1 [ Time Frame: From randomisation until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment. ]

Anti-tumor activity as determined by the DCR. Radiological assessment of tumor response should be performed approximately every 9 ± 1 weeks in the first 12 months and approximately every 12 ± 1 weeks from screening until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.

Part B: Disease response as determined by Clinical Benefit Rate per RECIST Version 1.1 [ Time Frame: From randomisation until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment. ]

Anti-tumor activity as determined by the CBR. Radiological assessment of tumor response should be performed approximately every 9 ± 1 weeks in the first 12 months and approximately every 12 ± 1 weeks from screening until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.

Part B: Disease response as determined by overall survival [ Time Frame: From randomisation until the patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment. ]

Anti-tumor activity as determined by the OS.

Secondary Outcome Measures :

Part A: Pharmacokinetic parameters, including but not limited to Ctrough of BGB-A317 [ Time Frame: pre-dose and at 4 hours in Cycles 2 (each cycle is 21 days), 3 and 4 ]

Part A: Pharmacokinetic parameters, including but not limited to Cmax of BGB-290 [ Time Frame: pre-dose and at 4 hours in Cycles 2 (each cycle is 21 days), 3 and 4 ]

Part A: Pharmacokinetic parameters, including but not limited to Tmax of BGB-290 [ Time Frame: pre-dose and at 4 hours in Cycles 2 (each cycle is 21 days), 3 and 4 ]

Part A: Pharmacokinetic parameters, including but not limited to Ctrough of BGB-290 [ Time Frame: pre-dose and at 4 hours in Cycles 2 (each cycle is 21 days), 3 and 4 ]

Part A: Disease response as determined by Overall Response Rate per RECIST Version 1.1 [ Time Frame: From randomisation until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment. ]

Anti-tumor activity as determined by the ORR. Radiological assessment of tumor response should be performed approximately every 9 ± 1 weeks in the first 12 months and approximately every 12 ± 1 weeks from screening until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.

Part A: Disease response as determined by Progression Free Survival per RECIST Version 1.1 [ Time Frame: From randomisation until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment. ]

Anti-tumor activity as determined by the PFS. Radiological assessment of tumor response should be performed approximately every 9 ± 1 weeks in the first 12 months and approximately every 12 ± 1 weeks from screening until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.

Part A: Disease response as determined by Duration of Response per RECIST Version 1.1 [ Time Frame: From randomisation until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment. ]

Anti-tumor activity as determined by the DOR. Radiological assessment of tumor response should be performed approximately every 9 ± 1 weeks in the first 12 months and approximately every 12 ± 1 weeks from screening until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.

Part A: Disease response as determined by Disease Control Rate per RECIST Version 1.1 [ Time Frame: From randomisation until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment. ]

Anti-tumor activity as determined by the DCR. Radiological assessment of tumor response should be performed approximately every 9 ± 1 weeks in the first 12 months and approximately every 12 ± 1 weeks from screening until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.

Part A: Disease response as determined by Clinical Benefit Rate per RECIST Version 1.1 [ Time Frame: From randomisation until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment. ]

Anti-tumor activity as determined by the CBR. Radiological assessment of tumor response should be performed approximately every 9 ± 1 weeks in the first 12 months and approximately every 12 ± 1 weeks from screening until unequivocal PD is documented, the patient starts new anti-cancer therapies, patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment.

Part A: Disease response as determined by overall survival [ Time Frame: From randomisation until the patient withdraws consent from the trial, date of death from any cause, or completes a total of 2 years treatment. ]

Anti-tumor activity as determined by the OS.

Part A: Immunogenicity of BGB-A317 [ Time Frame: Blood for anti-BGB-A317 antibodies should be collected within 24 hours before the start of the first dose of BGB-A317 in Cycle 1, and Day 8 of Cycle 1, Day 1 of Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 9 and Cycle 17 ]

Part B: Safety and tolerability as assessed by the incidence and nature of AEs [ Time Frame: from the day of first administration of study drugs up to 30 days after the last administration of BGB-290 and up to 120 days after the last administration of BGB-A317 ]

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Ages Eligible for Study:

18 Years and older (Adult, Older Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Patients have voluntarily agreed to participate by giving written informed consent.

Patients who have the below specified histologically or cytologically confirmed malignancies that have progressed to the advanced or metastatic stage.

In Part A, the patients must have an advanced malignancy including but not limited to high-grade serous cancer of the ovary, fallopian tube, or peritoneum (EOC), triple negative breast cancer (TNBC), SCLC, primary peritoneal cancer, and any tumor likely to harbor DNA damage repair deficiencies susceptible to treatment with a PARP inhibitor or likely to be responsive to a PD-1 blocker.

In Part B, the patients recruited to one of the eight expansion arms must have advanced solid tumors of the following types:

• If HRD or BRCA1/2 mutation status is unknown or has not been previously evaluated, then the patient must undergo tissue screening using the Myriad myChoice® diagnostic test to determine eligibility.

iv. Arm 1b: Patients with relapsed, platinum-sensitive high grade epithelial, non-mucinous, ovarian cancer, fallopian tube, or primary peritoneal cancer (EOC) without either known deleterious or suspected deleterious germline or somatic BRCA1/2 mutations or without DNA HRD • If HRD or BRCA1/2 mutation status is unknown or has not been previously evaluated, then the patient must undergo tissue screening using the Myriad myChoice® diagnostic test to determine eligibility.

Arm 2: Patients with triple negative breast cancer must meet the following criteria:

i. Patients with either known deleterious or suspected deleterious germline or somatic BRCA1/2 mutations or with DNA HRD.

• If HRD or BRCA1/2 mutation status is unknown or has not been previously evaluated, then the patient must undergo tissue screening using the Myriad myChoice® diagnostic test to determine eligibility.

• Note: patients could have received additional therapy after the last platinum-containing regimen if the other eligibility criteria are met.

iii. Patients who have received ≤ 3 prior lines of therapy in the advanced or metastatic setting.

Arm 3: Patients with metastatic castration-resistant prostate cancer, including but not limited to mutations in HR pathways and/or defined by HRD algorithms, and must meet the following criteria:

i. Patients with either known deleterious or suspected deleterious germline or somatic BRCA1/2 mutations or with DNA HRD.

• If HRD or BRCA1/2 mutation status is unknown or has not been previously evaluated, then the patient must undergo tissue screening using the Myriad myChoice® diagnostic test to determine eligibility.

ii. The patient may be either chemotherapy-naïve, but must have received prior abiraterone acetate and/or enzalutamide treatment, or have previously had no more than two taxane-based chemotherapy regimens including docetaxel and carbazitaxel. If docetaxel is used more than once, this will be considered as one regimen.

iii. At least 2 weeks since the completion of prior flutamide, bicalutamide, and nilutimide, or enzalutamide and abiraterone treatment.

iv. At least 2 weeks from any radiotherapy, with the exception of a single fraction of radiotherapy for the purposes of palliation (confined to one field).

v. Documented prostate cancer progression with one of the following:

Surgically or medically castrated. The testosterone levels do not need to be checked if the patient has undergone surgical castration for >4 months. Patients receiving chemical castration should have testosterone levels checked at baseline and confirmed to be in the castrate levels (<0.5 ng/mL or 1.735 nM). In all cases the luteinizing hormone-releasing hormone (LHRH) antagonist/agonist is to be continued in these patients.

Patients with only non-measurable bone lesions must have disease progression based on PCWG3 with 2 or more new lesions or have prostate-specific antigen (PSA) progression before enrollment.

Arm 4: Patients with extensive-stage disease small cell lung cancer (SCLC) must meet the following criterion:

i. Patients received ≤ 2 prior lines of therapy.

Arm 5: Patients with HER2-negative gastric or gastroesophageal junction cancer must meet the following criterion:

i. Patients received ≤ 2 prior lines of therapy in the advanced or metastatic disease setting.

ii. Patients must have received prior platinum-based systemic chemotherapy.

Arm 7: Patients with advanced or metastatic pancreatic adenocarcinoma must meet the following criteria:

i. Patients must have received at least one line of platinum containing regimens in either an advanced or metastatic setting, unless the patient has known deleterious germline or somatic BRCA1/2 mutation prior to being screened (in which case they can be considered for the study if the patient has never received platinum-containing regimen), AND ii. Patients received ≤ 1 prior lines of therapy in the advanced or metastatic disease setting.

Arm 8: Patients with advanced or metastatic solid tumor malignancies must meet the following criterion:

i. Patients with at least 1 prior platinum-containing treatment in any treatment setting.

Patients who were treated with chemotherapy, radiotherapy, immunotherapy or any investigational therapies, if eligible, must have been completed at least 4 weeks or at least 5 half-lives (whichever is shorter, but no less than 3 weeks) before the study drug administration, and all AEs have either returned to baseline or stabilized. Prior therapies targeting PD-1, programmed death-ligand 1 (PD-L1), or PARP is exclusionary (See Exclusion Criterion 5).

Patients must have archival tumor tissue or agree to a tumor biopsy for mutation and biomarkers analysis unless previously discussed with sponsor's medical monitor or its designee (fresh tumor biopsies are recommended at baseline in patients with readily accessible tumor lesions and who consent to the biopsies). Patients with ovarian, fallopian tube, primary peritoneal, or breast cancer in Part A and all patients enrolled in Part B must also agree to provide fresh blood sample at the baseline for the evaluation of BRCA mutations and/or confirmation of prior BRCA results or other homologous reconstitution deficiency mutation even if it was previously tested.

Patients must have measurable or evaluable disease as defined per the RECIST v1.1 except patients with mCRPC.

Patients must be a male or female ≥ 18 years of age on the day of signing informed consent.

Patients must have an ECOG Performance Status (PS) ≤ 1.

Patients must have a life expectancy ≥12 weeks.

Patient must have adequate organ function as indicated by the following laboratory values independent of transfusion within 2 weeks:

Absolute neutrophil count (ANC) ≥ 1,500/mL

Platelets ≥ 100,000/mL

Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L

Serum creatinine ≤ 1.5 × upper limit of normal (ULN)

Serum total bilirubin ≤ 1.5 × ULN (On fractionation ≤ 90% of total bilirubin should be unconjugated. Total bilirubin must be <4 X ULN for patients with Gilbert's syndrome).

Female patients are eligible to enter and participate in the study if they are of:

a) Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who: i. has had a hysterectomy ii. has had a bilateral oophorectomy iii. has had a bilateral salpingectomy iv. is post menopausal (total cessation of menses for ≥ 1 year) b) Childbearing potential, has a negative serum pregnancy test at screening (within 7 days of the first investigational product administration), is not breast feeding, and uses highly effective contraception before study entry and throughout the study until 90 days after the last investigational product administration. Adequate contraception as recommended by the Clinical Trial Facilitation Group (CTFG)

Male patients are eligible to enter and participate in the study if they are vasectomized or agree to use of contraception during the study treatment period and for at least 90 days after the last dose investigational product.

Exclusion Criteria:

Platinum-resistant/refractory disease, defined as progressive disease at the first tumor assessment while receiving platinum-based chemotherapy or within 6 months after treatment (for patients in Part B; disease-specific expansion arms only).

Patient has history of severe hypersensitivity reactions to other monoclonal antibodies (mAbs).

Prior malignancy within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, or carcinoma in situ of the cervix or breast or bladder.

Symptomatic central nervous system (CNS) metastasis(es). Note: Baseline CT/MRI of the brain is required for SCLC patients enrolled in Arm 4. Patients with previously treated CNS metastasis(es) are eligible if the patients with previously treated CNS metastasis(es) are asymptomatic and radiographically/clinically stable and not requiring steroids within 4 weeks prior to first dose.

Note: Non-SCLC patients without clinical signs or symptoms of CNS involvement are not required to have a computed tomography (CT)/magnetic resonance imaging (MRI) scan of the brain unless it is considered standard of care.

Note: Patient are permitted to enroll if they have controlled celiac disease, vitiligo, eczema, psoriasis, controlled Type I diabetes mellitus, endocrine deficiencies (including hypothyroidism) managed with replacement hormones including low-dose (≤10 mg/day prednisone equivalents) corticosteroids. Patients with rheumatological autoimmune diseases that are frequently limited in severity such as rheumatoid arthritis and Sjogren's syndrome are permitted to enroll if they do not require treatment with a non-biologic or biologic disease modifying anti-rheumatic drug (DMARDs), e.g. cyclophosphamide or adalimumab. All patients with an autoimmune rheumatological disease require evaluation for severity and target organ involvement.

Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 2 weeks of the study drug administration.

Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events (AEs).

Inability to swallow oral medications (capsules and tablets) without chewing, breaking, crushing, opening or otherwise altering the product formulation. Patients should not have gastrointestinal illnesses that would preclude the absorption of BGB-290, which is an oral agent.

Has been administered a live vaccine within 4 weeks (28 days) of initiation of study therapy. Patients are eligible if 28 days have elapsed since receipt of vaccine and initiation of study treatment. (NOTE: seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines; and are not allowed).

Any of the following cardiovascular criteria:

Current evidence of cardiac ischemia

Current symptomatic pulmonary embolism

Acute myocardial infarction ≤6 months prior to Day 1

Heart failure of New York Heart Association Classification III or IV ≤6 months prior to Day 1